rs61733680

Variant names:

• chr13-51974592-T-C
• rs61733680
• NM_000053.4:c.628A>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 1P and 9B. PP2 BP4_Strong BP6 BS1

The NM_000053.4(ATP7B):​c.628A>G​(p.Ile210Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000336 in 1,613,996 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I210F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0018 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00018 (0 hom.)
• Consequence: ATP7B NM_000053.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:6
• Conservation: PhyloP100: 0.00300
• Publications: 4 publications found

Genes affected

ATP7B (HGNC:870): (ATPase copper transporting beta) This gene is a member of the P-type cation transport ATPase family and encodes a protein with several membrane-spanning domains, an ATPase consensus sequence, a hinge domain, a phosphorylation site, and at least 2 putative copper-binding sites. This protein is a monomer, and functions as a copper-transporting ATPase which exports copper out of the cells, such as the efflux of hepatic copper into the bile. Alternate transcriptional splice variants, encoding different isoforms with distinct cellular localizations, have been characterized. Mutations in this gene have been associated with Wilson disease which is characterized by copper accumulation. [provided by RefSeq, Dec 2019]

ATP7B Gene-Disease associations (from GenCC):

• Wilson disease

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 198 curated pathogenic missense variants (we use a threshold of 10). The gene has 32 curated benign missense variants. Gene score misZ: -0.88091 (below the threshold of 3.09). Trascript score misZ: 0.82063 (below the threshold of 3.09). GenCC associations: The gene is linked to Wilson disease.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0053409934).
• BP6: Variant 13-51974592-T-C is Benign according to our data. Variant chr13-51974592-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 92390.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00184 (281/152320) while in subpopulation AFR AF = 0.00652 (271/41582). AF 95% confidence interval is 0.00588. There are 0 homozygotes in GnomAd4. There are 138 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000053.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP7B	NM_000053.4	MANE Select	c.628A>G	p.Ile210Val	missense	Exon 2 of 21	NP_000044.2	P35670-1
	ATP7B	NM_001406511.1		c.628A>G	p.Ile210Val	missense	Exon 3 of 22	NP_001393440.1	P35670-1
	ATP7B	NM_001406512.1		c.628A>G	p.Ile210Val	missense	Exon 3 of 22	NP_001393441.1	P35670-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP7B	ENST00000242839.10	TSL:1 MANE Select	c.628A>G	p.Ile210Val	missense	Exon 2 of 21	ENSP00000242839.5	P35670-1
	ATP7B	ENST00000634844.1	TSL:1	c.628A>G	p.Ile210Val	missense	Exon 2 of 21	ENSP00000489398.1	B7ZLR4
	ATP7B	ENST00000418097.7	TSL:1	c.628A>G	p.Ile210Val	missense	Exon 2 of 20	ENSP00000393343.2	F5H748

Frequencies

GnomAD3 genomes AF: 0.00185 AC: 281 AN: 152202 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00654

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.000469 AC: 117 AN: 249404 AF XY: 0.000325

Gnomad AFR exome AF: 0.00620

Gnomad AMR exome AF: 0.000551

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000179 AC: 261 AN: 1461676 Hom.: 0 Cov.: 34 AF XY: 0.000153 AC XY: 111 AN XY: 727150

African (AFR) AF: 0.00616 AC: 206 AN: 33426

American (AMR) AF: 0.000447 AC: 20 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111914

Other (OTH) AF: 0.000480 AC: 29 AN: 60384

GnomAD4 genome AF: 0.00184 AC: 281 AN: 152320 Hom.: 0 Cov.: 33 AF XY: 0.00185 AC XY: 138 AN XY: 74488

African (AFR) AF: 0.00652 AC: 271 AN: 41582

American (AMR) AF: 0.000196 AC: 3 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68016

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.000649 Hom.: 2

Bravo AF: 0.00202

ESP6500AA AF: 0.00610 AC: 24

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000620 AC: 75

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	2	Wilson disease (5)
-	1	2	not provided (3)
-	-	1	ATP7B-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.30	T
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.33
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.0053	T
MetaSVM	Benign	-0.41	T
MutationAssessor	Benign	-0.33	N
PhyloP100		0.0030
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.40	N
REVEL	Benign	0.20
Sift	Benign	0.52	T
Sift4G	Benign	0.84	T
Polyphen		0.0080	B
Vest4		0.099
MVP		0.55
MPC		0.057
ClinPred		0.025	T
GERP RS		4.6
PromoterAI		0.024	Neutral
Varity_R		0.061
gMVP		0.35
Mutation Taster		=71/29	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs61733680; hg19: chr13-52548728;